Process for preparation of 4-sulfonylthio azetidinone derivatives

ABSTRACT

A process for preparing an azetidinone derivative represented by the formula ##STR1## wherein R 1  is hydrogen, halogen or lower alkoxy, R 2  is hydrogen, halogen, lower alkoxy, amino or a group ##STR2## (in which R 5  is substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, substituted or unsubstituted phenoxymethyl, or substituted or unsubstituted benzoyl), or R 1  and R 2 , when taken together, are carbonyl, R 3  is substituted or unsubstituted phenyl, and R 4  is hydrogen, optionally substituted hydrocarbon residue or acyl, silyl, sulfonyl or phosphonyl derived from inorganic acid or organic acid, the process comprising reacting a dithioazetidinone derivative represented by the formula ##STR3## wherein R 1 , R 2  and R 4  are as defined above and R 9  is substituted or unsubstituted, nitrogen-containing aromatic heterocyclic residue with a compound represented by the formula 
     
         R.sup.3 SO.sub.2 SR.sup.9                                  (VII) 
    
     wherein R 3  and R 9  are as defined above.

This application is a continuation of application Ser. No. 675,578 filed Nov. 28, 1984, now abandoned.

This invention relates to a process for preparing azetidinone derivatives.

The azetidinone derivatives prepared by the process of the present invention are represented by the formula ##STR4## wherein R¹ is hydrogen, halogen or lower alkoxy, R² is hydrogen, halogen, lower alkoxy, amino or a group ##STR5## in which R⁵ is substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, substituted or unsubstituted phenoxymethyl, or substituted or unsubstituted benzoyl), or R¹ and R², when taken together, are carbonyl, R³ is substituted or unsubstituted phenyl, and R⁴ is hydrogen, optionally substituted hydrocarbon residue or acyl, silyl, sulfonyl or phosphonyl derived from inorganic acid or organic acid.

The azetidinone derivatives of the formula (I) are useful as the intermediates for synthesizing β-lactam antibiotics and can be made into a variety of β-lactam antibiotics depending on the selection of substituents. For example, an azetidinone derivative of the formula (I) wherein R⁴ is a group ##STR6## (in which R⁶ is hydrogen or carboxy protecting group) can be converted into a cephalosporin compound of the formula (III) by the process disclosed in Tetrahedron Letters, 23, 2187 (1982) which is shown in the following reaction scheme. ##STR7##

An azetidinone derivative of the formula (I) wherein R⁴ is hydrogen, silyl, sulfonyl or phosphonyl can be made into various monocyclic β-lactam antibiotics.

Conventional processes for preparing azetidinone derivatives of the formula (I) are described, for example, in Japanese Unexamined Patent Publication (Kokai) No. 129,590/1975. This process comprises, as indicated below by a reaction equation, reacting an azetidinone derivative of the formula (IV) with a heavy metal salt of sulfinic acid of the formula (V) to obtain an azetidinone derivative of the formula (Ib). ##STR8##

In the foregoing reaction equation, R³ and R⁶ are as defined above, R^(1') is hydrogen, R^(2') is amino or a group --NHR⁸ (wherein R⁸ is acyl), R⁷ is an aromatic heterocyclic group, aliphatic thioacyl group, aromatic thioacyl group, aromatic aliphatic thioacyl group or alicyclic thioacyl group, M is heavy metal such as copper, silver, mercury, tin or the like and n is the valence of heavy metal. However, the above process, when commercially carried out, involves the disadvantage of using a heavy metal salt of sulfinic acid of the formula (V) which is harmful or expensive.

It is an object of the present invention to provide a commercially advantageous process for preparing the azetidinone derivatives of the formula (I).

It is another object of the invention to provide a process for preparing the azetidinone derivative of the formula (I) without use of a heavy metal salt of sulfinic acid which is harmful or expensive.

It is a further object of the invention to provide a process for preparing the azetidinone derivative of the formula (I) with a high purity and in a high yield by carrying out a simple procedure.

These objects and other features of the present invention will become more apparent from the following description.

According to the present invention, the azetidinone derivative of the formula (I) can be prepared by reacting a dithioazetidinone derivative represented by the formula ##STR9## wherein R¹, R² and R⁴ are as defined above and R⁹ is substituted or unsubstituted, nitrogen-containing aromatic heterocyclic residue with a compound represented by the formula

    R.sup.3 SO.sub.2 SR.sup.9                                  (VII)

wherein R³ and R⁹ are as defined above.

Examples of the halogen atoms represented by R¹ in the formulae (I) and (VI) are F, Cl, Br, I and the like. Exemplary of the lower alkoxy groups represented by R¹ are those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, iopropoxy, butoxy, tert-butoxy, etc.

Examples of the halogen atoms represented by R² in the formulae (I) and (VI) are F, Cl, Br, I and the like. Illustrative of the lower alkoxy groups represented by R² are those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy, etc. Examples of the substituted phenyl groups represented by R⁵ are phenyl substituted with 1 to 3 C₁ -C₄ alkyl groups such as tolyl; phenyl substituted with 1 to 3 halogen atoms such as 4-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 4-bromophenyl and 2,4-dibromophenyl; phenyl substituted with 1 to 3 C₁ -C₄ alkoxy groups such as 4-methoxyphenyl, 2,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl; phenyl substituted with 1 to 3 nitro groups such as 4-nitrophenyl and 2,4-dinitrophenyl; etc. Examples of the substituted phenylmethyl groups represented by R⁵ are phenylmethyl substituted with 1 to 3 C₁ -C₄ alkyl groups on the phenyl ring such as tolylmethyl; phenylmethyl substituted with 1 to 3 halogen atoms on the phenyl ring such as 4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,4,6-trichlorophenylmethyl, 4-bromophenylmethyl and 2,4-dibromophenylmethyl; phenylmethyl substituted with 1 to 3 C₁ -C₄ alkoxy groups on the phenyl ring such as 4-methoxyphenylmethyl, 2,4-dimethoxyphenylmethyl and 3,4,5-trimethoxyphenylmethyl; phenylmethyl substituted with 1 to 3 nitro groups on the phenyl ring such as 4-nitrophenylmethyl and 2,4-dinitrophenylmethyl; phenylmethyl having methylene substituted with halogen, hydroxy, hydroxyimino, C₁ -C₄ alkoxyimino, amino or the like such as phenyldichloromethyl, phenylhydroxymethyl, phenylhydroxyiminomethyl, phenylmethoxyiminomethyl, phenylaminomethyl and phenylacetoxymethyl; etc. Examples of the substituted phenoxymethyl groups represented by R⁵ are phenoxymethyl substituted with 1 to 3 C₁ -C₄ alkyl groups on the phenyl ring such as tolyloxymethyl; phenoxymethyl substituted with 1 to 3 halogen atoms on the phenyl ring such as 4-chlorophenoxymethyl, 2,4-dichlorophenoxymethyl, 2,4,6-trichlorophenoxymethyl, 4-bromophenoxymethyl and 2,4-dibromophenoxymethyl; phenoxymethyl substituted with 1 to 3 C₁ -C₄ alkoxy groups on the phenyl ring such as 4-methoxyphenoxymethyl, 2,4-dimethoxyphenoxymethyl and 3,4,5-trimethoxyphenoxymethyl; phenoxymethyl substituted with 1 to 3 nitro groups on the phenyl ring such as 4-nitrophenoxymethyl and 2,4-dinitrophenoxymethyl; etc. Examples of the substituted benzoyl groups represented by R⁵ are benzoyl substituted with 1 to 3 C₁ -C₄ alkyl groups on the phenyl ring such as toluoyl; benzoyl substituted with 1 to 3 halogen atoms on the phenyl ring such as 4-chlorobenzoyl, 2,4-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 4-bromobenzoyl and 2,4-dibromobenzoyl; benzoyl substituted with 1 to 3 C₁ -C₄ alkoxy groups on the phenyl ring such as 4-methoxybenzoyl, 2,4-dimethoxybenzoyl and 3,4,5-trimethoxybenzoyl; benzoyl substituted with 1 to 3 nitro groups on the phenyl ring such as 4-nitrobenzoyl and 2,4-dinitrobenzoyl; etc.

Examples of the substituted phenyl represented by R³ in the formulae (I) and (VII) are phenyl substituted with 1 to 3 C₁ -C₄ alkyl groups such as tolyl and xylyl; phenyl substituted with 1 to 3 halogen atoms such as 4-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 4-bromophenyl and 2,4-dibromophenyl; phenyl substituted with 1 to 3 C₁ -C₄ alkoxy groups such as 4-methoxyphenyl, 2,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl; phenyl substituted with 1 to 3 nitro groups such as 4-nitrophenyl and 2,4-dinitrophenyl; etc.

The groups represented by R⁴ in the formulae (I) and (VI) are hydrogen, acyl, silyl, sulfonyl and phosphonyl derived from inorganic or organic acid, and optionally substituted hydrocarbon residue. Of these groups, the optionally substituted hydrocarbon residue is preferred. Exemplary of the substituted hydrocarbon residue are groups ##STR10## wherein R⁶ is hydrogen or carboxy protecting group. The wide range of carboxy protecting groups as disclosed in Theodora W. Greene: "Protective Groups in Organic Synthesis," Chapter 5 are usable in the present invention. Typical examples of the groups are phenyl C₁ -C₄ alkyl optionally having 1 to 3 substituents, e.g., C₁ -C₄ alkoxy, halogen, methylenedioxy, C₁ -C₄ alkyl or nitro on the phenyl ring such as benzyl, p-methoxybenzyl, trimethoxybenzyl, trimethoxydichlorobenzyl, piperonyl, diphenylmethyl, bis(p-methoxyphenyl)methyl, ditolylmethyl, phenyl-p-methoxyphenylmethyl, α-p-methoxyphenylmethyl, trityl, α-diphenylethyl, p-nitrobenzyl, o-nitrobenzyl and o,p-dinitrobenzyl; C₁ -C₄ alkyl which may have at least one substituent selected from halogen, phenyl substituted with 1 to 3 C₁ -C₄ alkoxy groups, benzoyl, benzoyl substituted with 1 to 3 halogen atoms on the phenyl ring, C₁ -C₄ alkoxy, C₁ -C₄ alkoxy substituted with 1 to 3 C₁ -C₄ alkoxy groups, benzyloxy, C₁ -C₄ alkanoyl and C₁ -C₄ alkoxycarbonyl, such as tert-butyl, trichloroethyl, α-p-methoxyphenyl-β-trichloroethyl, phenacyl, p-bromophenacyl, methoxymethyl, isopropoxymethyl, methoxyethoxymethyl, benzyloxymethyl and 1-methoxycarbonyl-2-oxopropyl; cumyl; fluorenyl; etc. Z¹ and Z² are the same or different and are each hydrogen, halogen, sulfur-containing group, oxygen-containing group, nitrogen-containing group or the like. Examples of the substituents represented by Z¹ and Z² are halogen such as bromine, chlorine and fluorine; sulfur-containing groups, e.g., C₁ -C₄ alkylthio such as methylthio and ethylthio, phenylthio optionally substituted with 1 to 5 nitro groups or halogen atoms on the phenyl ring such as phenylthio, p-nitrophenylthio and pentachlorophenylthio, 2-pyridylthio, 2-benzothiadiazolylthio, 1,3,4-thiadiazol-5-ylthio, 2-substituted-1,3,4-thiadiazol-5-ylthio, 1,2,3,4-tetrazol-5-ylthio, 1-substituted-1,2,3,4-tetrazol-5-ylthio, O-ethyldithiocarbonate, N,N-diethyldithiocarbamate, phenylsulfonyl and p-methylphenylsulfonyl; oxygen-containing groups, e.g., hydroxy, C₁ -C₄ alkoxy such as methoxy and ethoxy, C₁ -C₄ acyloxy such as acetoxy, benzoyloxy, nitrosoxy, nitriloxy, diphenylphosphonyloxy, methanesulfonate, N-morphonyl and diphenylmethyloxy; nitrogen-containing groups, e.g., di(C₁ -C₄ alkyl)amino such as dimethylamino, and piperidin-1-yl; etc.

Examples of the substituted or unsubstituted nitrogen-containing aromatic heterocyclic residue represented by R⁹ in the formulae (VI) and (VII) are those optionally having 1 to 3 substituents, e.g., with C₁ -C₄ alkyl, phenyl, C₁ -C₄ alkoxy, nitro or halogen, such as thiazol-2-yl, 4-methylthiazol-2-yl, 5-methylthiazol-2-yl, 4-phenylthiazol-2-yl, 5-phenylthiazol-2-yl, thiadiazol-2-yl, 5-methylthiadiazol-2-yl, 5-phenylthiadiazol-2-yl, 5-methoxycarbonylthiadiazol-2-yl, benzothiazol-2-yl, 4-methylbenzothiazol-2-yl, 6-methylbenzothiazol-2-yl, 5-methoxybenzothiazol-2-yl, 6-nitrobenzothiazol-2-yl, 5-chlorobenzothiazol-2-yl, benzoxazol-2-yl, 4-methylbenzoxazol-2-yl, 6-phenylbenzoxazol-2-yl, 5-methoxybenzoxazol-2-yl, 5-chlorobenzoxazol-2-yl, benzimidazol-2-yl, 5-methylbenzimidazol-2-yl, 6-chlorobenzoimidazol-2-yl, pyrimidin-2-yl, 5-methylpyrimidin-2-yl and 2-pyridyl, etc.

The dithioazetidinone derivatives of the formula (VI) used as one of the starting materials in the present invention are known and can be synthesized by various processes. The synthesizing processes using penicillin are disclosed, for example, in Tetrahedron Letters, 3001 (1973): Japanese Examined Patent Publication (Kokoku) No. 14665/1981; Japanese Unexamined Patent Publications (Kokai) Nos. 29587/1982, 59896/1982, 183793/1982 and 183794/1982; and The Collection of Drafted Research Reports for The 9th International Convention on Heterocycle, page 300 (1983). The derivatives of the formula (VI) can be produced also by a combination of processes described in these publications. These known processes are shown, for example, in the following reaction scheme. ##STR11## R⁶ and R⁹ are as defined above.

However, the dithioazetidinone derivatives of the formula (VI) as used in the present invention are not limited to those producible by these processes. An extensive range of dithioazetidinone derivatives of the formula (VI) produced by various processes including those other than the foregoing processes can be used as the starting material in the present invention.

The compounds of the formula (VII), namely the other starting material used in the present invention, are also known. The compound of the formula (VII) can be synthesized, for example, by the process disclosed in U.S. Pat. No. 3786063 which can be indicated in the following reaction equation. ##STR12##

In the foregoing reaction equation, R³ and R⁹ are as defined above.

According to the present invention, the dithioazetidinone derivative of the formula (VI) is reacted with the compound of the formula (VII) usually in a suitable solvent. Examples of the solvent which can be used in the present invention is not particularly limited as far as the solvent is capable of dissolving the compound of the formula (VI) and the compound of the formula (VII). Since these compounds need not be completely dissolved in the present invention, even solvents capable of partially dissolving them are usable. Useful solvents include organic solvents used singly or in conjunction with water. Examples of suitable organic solvents are ketones such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone; esters such as methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate and ethyl propionate; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, dichloroethane, dibromoethane and trichloroethane; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran and dioxane; nitroalkanes such as nitromethane, nitroethane and nitropropane; nitriles such as acetonitrile, propionitrile, butyronitrile and valeronitrile; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; etc. These organic solvents can be used singly or at least two of them are usable in admixture. The amount of the solvent is usually about 1 to about 400 times, preferably about 1 to 100 times, more preferably about 1 to about 50 times, the weight of the compound of the formula (VI).

The proportions of the compounds of the formulae (VI) and (VII) used in the present invention are not particularly limited and can be suitably determined over a wide range. Usually about 1 to about 5 moles, preferably about 1 to about 1.2 moles, of the compound of the formula (VII) is used per mole of the compound of the formula (VI).

The reaction of the present invention can be usually carried out at a temperature ranging from about -20° C. to the temperature at which the solvent used is refluxed. Preferred reaction temperature is in the range of 0° to about 80° C., preferably about 10° to about 40° C. The reaction time in the present invention varies depending on the reaction temperature, kinds of the compounds (VI) and (VII) and the other conditions, but usually ranges from about 0.1 to about 15 hours.

In the present invention, it is preferred to incorporate into the reaction system at least one kind of catalyst selected from a sulfinic acid of the formula

    R.sup.3 SO.sub.2 H                                         (VIII)

wherein R³ is as defined above or a salt thereof, a thiol of the formula

    R.sup.9 SH                                                 (IX)

wherein R⁹ is as defined above or a salt thereof, and a nucleophilic compound capable of producing R³ SO₂.sup.⊖ when reacted with the compound (VII). The presence of the foregoing catalyst in the reaction system results in the production of the desired compound (I) of higher purity in higher yields.

Examples of the substituted or unsubstituted phenyl represented by R³ in the sulfinic acid (VIII) are the same as those exemplified above. Examples of the sulfinic acid (VIII) as used above are benzenesulfinic acid, tolylsulfinic acid, xylylsulfinic acid, 4-chlorophenylsulfinic acid, 2,4-dichlorophenylsulfinic acid, 2,4,6-trichlorophenylsulfinic acid, 4-bromophenylsulfinic acid, 2,4-dibromophenylsulfinic acid, 4-methoxyphenylsulfinic acid, 2,4-dimethoxyphenylsulfinic acid, 3,4,5-trimethoxyphenylsulfinic acid, 4-nitrophenylsulfinic acid, 2,4-dinitrophenylsulfinic acid, etc. Examples of the salt of the sulfinic acid (VIII) as used above are salts of alkali metals such as lithium, sodium, potassium and rubidium, salts of alkaline earth metals such as magnesium, calcium, strontium and barium, ammonium salts such as ammonium, tetra (C₁ -C₄ alkyl)ammonium, e.g., tetramethylammonium, tetraethylammonium and trimethyl ethyl ammonium, pyridium salt, etc. Of these salts, an alkali metal salt is perferably used. Preferred examples of the alkali metal salts are sodium benzensulfinate, potassium benzenesulfinate, lithium benzenesulfinate, rubidium benzenesulfinate, sodium tolylsulfinate, potassium tolylsulfinate, sodium xylylsulfinate, sodium 4-chlorophenylsulfinate, potassium 4-chlorophenylsulfinate, sodium 2,4-dichlorophenylsulfinate, sodium 2,4,6-trichlorophenylsulfinate, sodium 4-bromophenylsulfinate, sodium 2,4-dibromophenylsulfinate, sodium 4-methoxyphenylsulfinate, potassium 4-methoxyphenylsulfinate, sodium 2,4-dimethoxyphenylsulfinate, sodium 3,4,5-trimethoxysulfinate, sodium 4-nitrophenylsulfinate, potassium 4-nitrophenylsulfinate, sodium 2,4-dinitrophenylsulfinate, etc. potassium 2,4-dinitrophenylsulfinate,

Examples of the substituted or unsubstituted, nitrogen-containing aromatic heterocyclic residue represented by R⁹ in the thiol (IX) are the same as those exemplified above. Examples of the thiol (IX) as used above are 2-thiazole thiol, 2-(4-methyl)thiazole thiol, 2-(5-methyl)thiazole thiol, 2-(4-phenyl)thiazole thiol, 2-(5-phenyl)thiazole thiol, 2-thiadiazole thiol, 2-(5-methyl)thiadiazole thiol, 2-(5-phenyl)thiadiazole thiol, 2-(5-methoxycarbonyl)thiadiazole thiol, 2-benzothiazole thiol, 2-(4-methyl)benzothiazole thiol, 2-(6-methyl)benzothiazole thiol, 2-(5-methoxy)benzothiazole thiol, 2-(4-nitro)benzothiazole thiol, 2-(6-nitro)benzothiazole thiol, 2-(5-chloro)benzothiazole thiol, 2-benzoxazole thiol, 2-(4-methyl)benzoxazole thiol, 2-(6-phenyl)benzoxazole thiol, 2-(5-methoxy)benzoxazole thiol, 2-(5-chloro)benzoxazole thiol, 2-benzimidazole thiol, 2-(6-methyl)benzimidazole thiol, 2-(6-chloro)benzimidazole thiol, 2-pyrimidine thiol, 2-(5-methyl)pyrimidine thiol, 2-pyridyl thiol, etc. Examples of the salt of the thiol (IX) as used above are salts of alkali metals such as lithium, sodium, potassium and rubidium, salts of alkaline earth metals such as magnesium, calcium, strontium and barium, ammonium salts such as ammonium, tetra(C₁ -C₄ alkyl)ammonium e.g., tetramethylammonium, tetraethylammonium and trimethyl ethyl ammonium, pyridium salts, etc. Of these salts, an alkali metal salt is preferably used. Preferred examples of the alkali metal salts are sodium 2-thiazole thiolate, sodium 2-(4-methyl)thiazole thiolate, sodium 2-(5-methyl)thiazole thiolate, sodium 2-(4-phenyl)thiazole thiolate, sodium 2-(5-phenyl)thiazole thiolate, sodium 2-thiadiazole thiolate, sodium 2-(5-methyl)thiadiazole thiolate, sodium 2-(5-phenyl)thiadiazole thiolate, sodium 2-(5-methoxycarbonyl)thiadiazole thiolate, sodium 2-benzothiazole thiolate, sodium 2-(6-methyl)benzothiazole thiolate, sodium 2-(5-methoxy)benzothiazole thiolate, sodium 2-(4-nitro)benzothiazole thiolate, sodium 2-(6-nitro)benzothiazole thiolate, sodium 2-(5-chloro)benzothiazole thiolate, sodium 2-benzoxazole thiolate, sodium 2-(4-methyl)benzoxazole thiolate, sodium 2-(6-phenyl)benzoxazole thiolate, sodium 2-(5-methoxy)benzoxazole thiolate, sodium 2-(5-chloro)benzoxazole thiolate, sodium 2-benzimidazole thiolate, sodium 2-(6-methyl)benzimidazole thiolate, sodium 2-(6-chloro)benzimidazole thiolate, sodium 2-pyrimidine thiolate, sodium 2-(5-methyl)pyrimidine thiolate, sodium 2-pyridyl thiolate, potassium 2-benzothiazole thiolate, potassium 2-(4-methyl)benzothiazole thiolate, potassium 2-(6-methyl)benzothiazole thiolate, potassium 2-(6-nitro)benzothiazole thiolate, potassium 2-(5-methoxy)benzothiazole thiolate, potassium 2-(5-methyl)thiadiazole thiolate, lithium 2-benzothiazole thiolate, rubidium 2-benzothiazole thiolate, etc.

Examples of useful nucleophilic compounds are water, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, butonal and inorganic or organic salts thereof; phenols such as phenol, cresol, p-methoxyphenol, p-nitrophenol and inorganic or organic salts thereof; thiols other than the compounds (IX) such as methanethiol, ethanethiol, propanethiol, thiophenol, thiocresol, p-nitrothiophenol and inorganic or organic salts thereof; sulfinic acids other than the compounds (VIII) such as methanesulfinic acid, ethanesulfinic acid, propanesulfinic acid and inorganic or organic salts thereof; carboxylic acids such as acetic acid, propionic acid and inorganic or organic salts thereof; etc. When an alcohol having 1 to 4 carbon atoms is used as a solvent, no catalyst is required because the alcohol acts as a nucleophilic compound.

The reaction of the present invention with the reaction system containing the aforesaid catalyst is shown in the following reaction equation. ##STR13##

In the foregoing reaction equation, R¹, R², R³, R⁴ and R⁹ are as defined above.

When the last one molecule of R³ SO₂.sup.⊖ or R⁹ S.sup.⊖ is present in the reaction system, the catalytic reaction as illustrated above can proceed between the compound (VI) and the compound (VII), thereby giving a compound (I).

More specifically, when a sulfinic acid (VIII) or a salt thereof is used as a catalyst, the sulfinic acid (VIII) or the salt thereof is reacted with a compound (VI) to form a compound (I) and a thiol (IX) or a salt thereof. The thiol (IX) or the salt thereof thus obtained is reacted with a compound (VII), producing a compound (X), respectively and regenerating a sulfinic acid (VIII) or a salt thereof. The compound (X) is precipitated as crystals due to its low solubility. The regenerated sulfinic acid (VIII) or the salt thereof is reacted with a compound (VI).

When a thiol (IX) or a salt thereof is used as a catalyst, the thiol (IX) or the salt thereof is reacted with a compound (VIII), affording a sulfinic acid (VIII) or a salt thereof and a compound (X). The compound (X), which has a low solubility, is deposited as crystals. The sulfinic acid (VIII) or the salt thereof is reacted with a compound (VI), producing a compound (I) and regenerating a thiol (IX) or a salt thereof.

When a sulfinic acid (VIII) or a salt thereof is used in conjunction with a thiol (IX) or a salt thereof, the foregoing reactions simultaneously proceed.

When the above-mentioned nucleophilic compound is used as a catalyst, the reaction proceeds in the same manner as in use of the sulfinic acid (VIII) or the salt thereof as a catalyst.

While reaction can proceed with a system containing one molecule of the catalyst, usually about 0.0001 to about 0.1 mole, preferably about 0.001 to about 0.05 mole, of the catalyst is used per mole of the compound (VI).

After the completion of the reaction, the azetidinone derivative (I) of the present invention can be separated from the reaction mixture by conventional methods such as filtration, centrifugation, distillation, extraction, etc. The azetidinone derivative (I) thus obtained is substantially pure, but can be easily purified by recrystallization, column chromatography or like means if further purification is needed.

According to the present invention, a desired compound (I) of high purity can be prepared in high yields without use of expensive or harmful heavy metal salt of sulfinic acid by carrying out a simple procedure. The process of the present invention has the following additional advantage. Although the process of the present invention gives a compound (X) as a by-product, the compound (X) of high purity can be recovered in high yields by a simple filtration and the recovered compound (X) is available as the starting material for synthesizing a compound (VII) which is used as the starting material in the present invention.

The present invention will be described below in more detail with reference to the following Examples to which, however, the present invention is limited in no way and in which the code Ph refers to phenyl.

EXAMPLE 1 ##STR14##

A 13.2 g quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 7.0 g of 2-benzothiazolyl benzenethiosulfonate was dissolved in 130 ml of acetone. To the solution were added 26 ml of water and then 20 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hours. The precipitated 2 -benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in benzene, washed with water and dried. The benzene was distilled off to give p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate. The compound thus obtained was purified by silica gel column chromatography, affording p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 93%. The NMR spectrum data of the compound were identical with those of the desired compound. Table 2 shows the NMR spectrum data of the compound.

EXAMPLE 2 ##STR15##

A 13.2 g quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 7.0 g of 2-benzothiazolyl benzenethiosulfonate was dissolved in 130 ml of acetone. To the solution were added 26 ml of water and then 20 mg of sodium 2-benzothiazolyl thiolate and the mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound were identical with those of the compound obtained in Example 1.

EXAMPLE 3 ##STR16##

A 263 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methoxybenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 147 mg of 5-methoxybenzothiazol-2-yl benzenethiosulfonate were dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 2 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hour. The precipitated 5-methoxybenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 96%. The NMR spectrum data of the compound were identical with those of the desired compound. Table 2 shows the NMR spectrum data of the compound.

EXAMPLE 4 ##STR17##

A 500 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methylthiadizol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 251 mg of 5-methylthiadiazol-2-yl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 5 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hours. The precipitated 5-methylthiadiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 89%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 3.

EXAMPLE 5 ##STR18##

A 500 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 314 mg of 2-benzothiazolyl p-toluenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 2 mg of sodium p-toluenesulfinate and the mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving methyl 2-[3-phenylacetamido-4-(p-toluenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 95%. The NMR spectrum data of the compound were identical with those of the desired compound. Table 2 shows the NMR spectrum data of the compound.

EXAMPLE 6 ##STR19##

A 500 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 260 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution was added 2 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 12 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 90%. The NMR spectrum data of the compound were identical with those of the compound produced in Example 1.

EXAMPLE 7

The same procedure as in Example 6 was repeated with the exception of using chloroform in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 86%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 8

The same procedure as in Example 6 was repeated with the exception of using benzene in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 82%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 9

The same procedure as in Example 6 was repeated with the exception of using acetonitrile in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 10

The same procedure as in Example 6 was repeated with the exception of using ethyl acetate in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained with identical with those of the compound produced in Example 1.

EXAMPLE 11

The same procedure as in Example 6 was repeated with the exception of using nitromethane in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 90%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 12

The same procedure as in Example 6 was repeated with the exception of using dioxane in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 82%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 13

The same procedure as in Example 6 was repeated with the exception of using tetrahydrofuran in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 67%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 14

A 500 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 260 mg of 2-benzothiazolyl benzenethiosulfonate were placed into a 260 mg reactor in which 10 ml of isopropyl alcohol was then introduced. The mixture was stirred at room temperature for 12 hours during which the reactants did not completely dissolve, remaining as suspended. The insolubles were filtered off and washed with 10 ml of acetone. The washing and the filtrate were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 95%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 15

The same procedure as in Example 14 was repeated with the exception of using methanol in place of isopropyl alcohol as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 92%. The NMR spectrum data of the compound thus obtained with identical with those of the compound produced in Example 1.

EXAMPLE 16 ##STR20##

A 200 mg quantity of 3,4,5-trimethoxybenzyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 97 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 3 ml of acetone. To the solution were added 0.3 ml of water and then 2 mg of potassium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, givng 3,4,5-trimethoxybenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 92%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 17 ##STR21##

A 1.0 g quantity of p-methoxybenzyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 488 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 5 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving p-methoxybenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 96%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 18 ##STR22##

A 198 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(6-nitrobenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 113 mg of 6-nitrobenzothiazol-2-yl benzenethiosulfonate were dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 8 hours. The precipitated 6-nitrobenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 79%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 3.

EXAMPLE 19 ##STR23##

A 1.03 g quantity of 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-[3-phenoxyacetamido-4-(4-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 448 mg of 4-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 8 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 4-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 86%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 20 ##STR24##

A 1.23 g quantity of p-bromophenacyl 2-[3-phenoxyacetamido-4-(6-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 572 mg of 6-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 6-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving p-bromophenacyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 94%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below shows the data thereof.

EXAMPLE 21 ##STR25##

A 307 mg quantity of methoxyethoxymethyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 164 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 4 ml of acetone. To the solution were added 0.8 ml of water and then 1 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 1.5 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving methoxyethoxy 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 83%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 22 ##STR26##

A 329 mg quantity of methoxymethyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyl-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 190 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 4 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving methoxymethyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoatein a yield of 72%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below shows the data thereof.

EXAMPLE 23 ##STR27##

A 1.15 g quantity of 9-fluorenyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 545 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 20 ml of acetone. To the solution were added 4 ml of water and then 10 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 2 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving 9-fluorenyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 24 ##STR28##

A 7.16 g quantity of 9-fluorenyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 3.86 g of 2-benzothiazolyl benzenethiosulfonate were dissolved in 100 ml of acetone. To the solution were added 20 ml of water and then 10 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 1 hour. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving 9-fluorenyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 89%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 25 ##STR29##

A 500 mg quantity of p-nitrobenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 254 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 2 mg of sodium benzenesulfonate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving p-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 26 ##STR30##

A 500 mg quantity of o-nitrobenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 254 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 2 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving o-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 27 ##STR31##

A 500 mg quantity of 1-methoxycarbonyl-2-oxopropyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 263 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 2 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving 1-methoxycarbonyl-2-oxopropyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 87%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 28 ##STR32##

A 500 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 334 mg of 2-benzothiazolyl p-chlorobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving methyl 2-[3-phenylacetamido-4-(p-chlorobenzenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 72%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 29 ##STR33##

A 500 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 344 mg of 2-benzothiazolyl p-nitrobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving methyl 2-[3-phenylacetamido-4-(p-nitrobenzenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 58%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 30 ##STR34##

A 500 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 344 mg of 2-benzothiazolyl o-nitrobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving methyl 2-[3-phenylacetamido-4-(o-nitrobenzenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 75%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 31 ##STR35##

A 500 mg quantity of benzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 314 mg of 2-benzothiazolyl p-nitrobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving benzyl 2-[3-phenylacetamido-4-(p-nitrobenzenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 70%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 32 ##STR36##

A 500 mg quantity of benzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 300 mg of 2-benzothiazolyl p-methoxybenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving benzyl 2-[3-phenylacetamido- 4-(p-methoxybenzenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 88%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLE 33 ##STR37##

A 200 mg quantity of p-nitrobenzyl 2-[3-methoxy-3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 102 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 3 ml of acetone. To the solution were added 0.3 ml of water and then 1 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving p-nitrobenzyl 2-[3-methoxy-3-phenylacetamido-4-(2-benzothiazolylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 90%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.

EXAMPLES 34 TO 36

The compounds as shown below in Table 1 were produced by following the general procedure of Example 1. Table 2 below lists the NMR spectrum data of the compounds thus obtained.

                                      TABLE 1                                      __________________________________________________________________________      ##STR38##                                                                                                                 Yield                              Ex. No.                                                                             R.sup.1                                                                          R.sup.2 R.sup.9   R.sup.4 R.sup.3    (%)                                __________________________________________________________________________     34   H                                                                                 ##STR39##                                                                              ##STR40##                                                                                ##STR41##                                                                              ##STR42## 93                                 35   " "       "         "                                                                                       ##STR43## 96                                 36   " "       "         H                                                                                       ##STR44## 75                                 __________________________________________________________________________

EXAMPLE 37

The same procedure as in Example 1 was repeated with the exception of using 17 mg of benzenesulfinic acid in place of 20 mg of sodium benzenesulfinate as a catalyst, producing p-methoxybenzyl-2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-betenoate in a yield of 87%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

EXAMPLE 38

The same procedure as in Example 1 was repeated with the exception of using 20 mg of benzothiazole thiol in place of 20 mg of sodium benzenesulfinate as a catalyst, producing p-methoxybenzyl-2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

                                      TABLE 2                                      __________________________________________________________________________      ##STR45##                                                                     R.sup.1                                                                             R.sup.2  R.sup.4         R.sup.3    NMR (CDCl.sub.3, δ,             __________________________________________________________________________                                              J=Hz)                                       ##STR46##                                                                               ##STR47##      Ph         1.71(s, 3H), 3.54(s, 2H),                                                      3.78(s, 3H), 4.45(s, 1H),                                                      4.69(s, 1H), 4.72(bs, 1H),                                                     5.02(s, 1H), 5.06(dd, 1H, J=4.0                                                and 6.5), 5.70(d, 1H, J=4.0),                                                  5.90(d, 1H, J=6.5), 6.82(d, 2H,                                                J=7.0), 7.00-7.85(m, 12H)             H                                                                                    ##STR48##                                                                               ##STR49##      Ph         1.78(s, 3H), 4.37 and 4.42(ABq,                                                2H, J=12.0), 4.55(s, 1H),                                                      4.79(s, 1H), 4.82(bs, 1H),                                                     5.14(s, 2H), 5.27(dd, 1H, J=4.0                                                and 7.0), 5.87(d, 1H, J=4.0),                                                  6.75-7.90(m, 16H)                     H                                                                                    ##STR50##                                                                               ##STR51##                                                                                      ##STR52## 1.74(s, 3H), 2.40(s, 3H),                                                      3.50(s, 2H), 3.71(s, 3H),                                                      4.64(s, 1H), 4.70(s, 1H),                                                      4.89(s, 1H), 5.05(dd, 1H, J=5                                                  and 8), 5.78(d, 1H, J=5),                                                      6.52(d, H, J=8), 7.22(s, 5H,                                                   7.30(d, 2H, J=9), 7.68(d, 2H),                                                 J=9)                                  H                                                                                    ##STR53##                                                                               ##STR54##      Ph         1.79(s, 3H), 3.85(s, 9H), 4.35                                                 and 4.41(ABq, 2H, J=12.5),                                                     4.62(s,1H), 4.80(s, 1H),                                                       4.84(bs, 1H), 5.08(s, 2H),                                                     5.26(dd, 1H, J=4 and 7), 5.84                                                  (d, 1H, J=4), 6.54(s, 2H),                                                     6.75-7.90(m, 11H)                     H                                                                                    ##STR55##                                                                               ##STR56##      Ph         1.76(s, 3H), 3.77(s, 3H), 4.34                                                 and 4.40(ABq, 2H, J=12), 4.53(s,                                               1H), 4.76(s, 1H), 4.79(bs, 1H),                                                5.07(s, 2H), 5.27(dd, 1H, J=4                                                  and 6.5), 5.86(d, 1H, J=4),                                                    6.65-7.90(m, 15H)                     H                                                                                    ##STR57##                                                                               ##STR58##      Ph         1.76(s, 3H), 3.89(s, 6H),                                                      3.94(s, 3H), 4.36 and 4.41(ABq,                                                2H, J=12), 4.60(s, 1H), 4.78(bs,                                               1H), 4.80(s, 1H), 5.24(dd, 1H,                                                 J=4 and 6.5), 5.38(s, 2H),                                                     5.88(s, 2H), 6.75-7.90(m, 11H)        H                                                                                    ##STR59##                                                                               ##STR60##      Ph         1.85(s, 3H), 4.38 and 4.44(ABq,                                                2H, J=12), 4.90(s, 1H), 4.96(s,                                                2H), 5.28 and 5.34(ABq, 2H,                                                    J=12), 5.35(dd, 1H, J=4 and                                                    6.5), 5.85(d, 1H, J=4),                                                        6.75-7.95(m, 15H)                     H                                                                                    ##STR61##                                                                               ##STR62##      Ph         1.82(s, 3H), 3.36(s, 3H),                                                      3.40-3.65(m, 2H), 3.65- 3.90(m,                                                2H),4.36 and 4.41(ABq, 2H,                                                     J=12), 4.69(s, 1H), 4.79(s, 1H),                                               4.94(bs, 1H), 5.15-5.60 (m, 3H),                                               5.90(d, 1H, J=4), 6.75-8.00(m,                                                 11H)                                  H                                                                                    ##STR63##                                                                               ##STR64##      Ph         1.85(s, 3H), 3.46(s, 3H), 4.41                                                 and 4.46(ABq, 2H, J=12), 4.71(s,                                               1H), 4.82(s, 1H), 4.95(bs, 1H),                                                5.10-5.40(m, 3H), 5.91(d, 1H,                                                  J=4.7), 6.80-8.00(m, 1H)              H                                                                                    ##STR65##                                                                               ##STR66##      Ph         1.78(s, 3H), 4.39 and 4.44(ABq,                                                2H, J=12), 4.76(s, 1H), 4.85(s,                                                1H), 4.88(bs, 1H), 5.34(dd, 1H,                                                J=4.7 and 8.2), 5.87(d, 1H,                                                    J=4.7) 6.76(s, 1H), 6.80-7.90(m,                                               19H)                                  H                                                                                    ##STR67##                                                                               ##STR68##      Ph         1.76(s, 3H), 3.57(s, 2H),                                                      4.71(s, 1H), 4.82(s, 1H),                                                      4.84(s, 1H), 5.16(dd, 1H, J=4.7                                                and 8.1), 5.76(d, 1H, J=4.7),                                                  6.50(d, 1H, J=8.1), 6.74(s, 1H),                                               7.05-7.90(m, 18H)                     H                                                                                    ##STR69##                                                                               ##STR70##      Ph         1.78(s, 3H), 3.56(s, 2H),                                                      4.57(s, 1H), 4.76(s, 1H),                                                      4.88(bs, 1H), 5.11(dd, 1H, J=4                                                 and 7), 5.23(s, 2H), 5.72(d, 1H,                                               J=4), 6.06(d, 1H, J=7),                                                        7.00-8.00(m, 12H), 8.19(d, 2H,                                                 J=7)                                  H                                                                                    ##STR71##                                                                               ##STR72##      Ph         1.78(s, 3H), 3.56(s, 2H),                                                      4.60(s, 1H), 4.76(s, 1H),                                                      4.87(bs, 1H), 5.12(dd, 1H, J=4                                                 and 6.5), 5.53(s, 2H), 5.64(d,                                                 1H, J=4), 6.20(d, 1H, J=6.5),                                                  7.10-8.20(m, 14H)                     H                                                                                    ##STR73##                                                                               ##STR74##      Ph         1.84(s, 3H), 2.35(s, 3H),                                                      3.83(s, 3H), 4.38 and 4.45(ABq,                                                2H, J=11), 4.80-5.05(m, 3H),                                                   5.38 (dd, 1H, J=4 and 7),                                                      5.55(s, 1H), 5.85(d, 1H, J=4.0),                                               6.75-8.00(m, 11H)                     H                                                                                    ##STR75##                                                                               ##STR76##                                                                                      ##STR77## 1.78(s, 3H), 3.51(bs, 2H),                                                     3.70(s, 3H), 4.61(bs, 1H),                                                     4.76(s, 1H), 4.86(bs, 1H),                                                     5.06(dd, 1H, J=5 and 8), 5.83(d,                                               1H, J=5), 7.14(d, 1H, J=8),                                                    7.23(s, 5H), 7.43(d, 2H, J=8),                                                 7.81(d, 2H, J=8)                      H                                                                                    ##STR78##                                                                               ##STR79##                                                                                      ##STR80## 1.80(s, 3H), 3.52(bs, 2H),                                                     3.70(s, 3H), 4.55(bs, 1H),                                                     4.79(s, 1H), 4.87(bs, 1H),                                                     5.03(dd, 1H, J=5 and 8), 5.87(d,                                               1H, J=5), 6.73(d, 1H, J=8),                                                    7.22(s, 5H), 7.94(d, 2H, J=9),                                                 8.24(d, 2H, J=9)                      H                                                                                    ##STR81##                                                                               ##STR82##                                                                                      ##STR83## 1.80(s, 3H), 3.48(bs, 2H),                                                     3.70(s, 3H), 4.64(bs, 1H),                                                     4.80(s, 1H), 4.88(bs, 1H),                                                     5.13(dd, 1H, J=5 and 8), 6.06(d,                                               1H, J=5), 6.88(d, 1H, J=8),                                                    7.17(s, 5H), 7.60-8.20(m, 4H)         H                                                                                    ##STR84##                                                                               ##STR85##                                                                                      ##STR86## 1.75(s, 3H), 3.50(s, 2H),                                                      4.76(bs, 1H), 4.84(s, 1H),                                                     4.92(bs, 1H), 5.10(dd, 1H), J=5                                                and 8), 5.12(s, 2H), 5.92(d, 1H,                                               J=5), 6.91(d, 1H, J=8), 7.20(s,                                                5H), 7.30(s, 5H), 7.87(d, 2H,                                                  J=9), 8.18(d, 2H, J=9)                H                                                                                    ##STR87##                                                                               ##STR88##                                                                                      ##STR89## 1.75(s, 3H), 3.50(s, 2H),                                                      3.79(s, 3H), 4.65(bs, 1H),                                                     4.77(s, 1H), 4.85(bs, 1H),                                                     5.12(dd, 1H, J=5 and 8), 5.13(s,                                               2H), 5.73(d, 1H, J=5), 6.63(d,                                                 1H, J=8), 6.87(d, 2H, J=9),                                                    7.20(s, 5H), 7.29(s, 5H),                                                      7.67(d, 2H, J=9)                      CH.sub.3 O                                                                           ##STR90##                                                                               ##STR91##      Ph         1.79(s, 3H), 3.46(s, 3H),                                                      3.61(s, 2H), 4.57(s, 1H),                                                      4.81(s, 1H), 4.88(bs, 1H),                                                     5.23(s, 2H), 5.29(s, 1H),                                                      6.00(bs, 1H), 7.10-7.90(m, 12H),                                               .17(d, 2H, J=9)                       H                                                                                    ##STR92##                                                                               ##STR93##                                                                                      ##STR94## 1.91(s, 3H), 2.15(s, 3H),                                                      3.60(s, 2H), 4.60- 4.80(m, 3H),                                                5.83(d, 1H, J=5Hz), 7.20(m, 8H),                                               .66 (d, 2H, J=9Hz)                    H                                                                                    ##STR95##                                                                               ##STR96##                                                                                      ##STR97## 1.90(s, 3H), 2.13(s, 3H),                                                      3.50(s, 2H), 3.75(s, 3H),                                                      4.60-4.80(m, 3H), 5.85(d, 1H,                                                  J=4.5Hz), 6.84(d, 2H, J=7Hz),                                                  7.20(m, 6H), 7.77(d, 2H, J=7Jz)       H                                                                                    ##STR98##                                                                              H                                                                                               ##STR99## 2.50(s, 3H), 3.63(s, 2H),                                                      5.20-5.50(m, 2H), 7.20-7.80(m,                                                 11H)                                  __________________________________________________________________________ 

We claim:
 1. A process for preparing an azetidinone derivative represented by the formula ##STR100## wherein R¹ is hydrogen, halogen or lower alkoxy, R² is a hydrogen, halogen, lower alkoxy, amino or a group ##STR101## (in which R⁵ is substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, substituted or unsubstituted phenoxymethyl, or substituted or unsubstituted benzoyl), or R¹ and R², when taken together with the carbon atom in the azetidinone ring, are carbonyl, R³ is substituted or unsubstituted phenyl, and R⁴ is hydrogen or one of the following groups ##STR102## (in which R⁶ is hydrogen or a carboxy protecting group, and Z¹ and Z² are the same or different and represent hydrogen, halogen, C₁ -C₄ alkylthio, phenylthio optionally substituted with 1 to 5 nitro groups or halogen atoms on the phenyl ring, 2-pyridylthio, 2-benzothiadiazolylthio, 1,3,4-thiadiazol-5-ylthio, 1,2,3,4-tetrazol-5-ylthio, O-ethyldithiocarbonate, N,N-diethyldithiocarbamate, phenyl-sulfonyl, p-methylphenylsulfonyl, hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ acyloxy, benzyloxy, nitrosoxy, diphenylphosphonyloxy, methanesulfonate, diphenylmethyloxy, di(C₁ -C₄ alkyl)amino or piperidin-1-yl), the process comprising reacting a dithioazethidinone derivative represented by the formula ##STR103## wherein R¹, R² and R⁴ are as defined above and R⁹ is a substituted or unsubstituted, nitrogen-containing aromatic heterocyclic residue with a compound represented by the formula

    R.sup.3 SO.sub.2 SR.sup.9                                  (VII)

wherein R³ and R⁹ are as defined above.
 2. A process as defined in claim 1 in which R¹ in the dithioazetidinone derivative of the formula (VI) is hydrogen, F, Cl, Br, I or C₁ -C₄ alkoxy, R² is hydrogen, F, Cl, Br, I, C₁ -C₄ alkoxy, amino or a group ##STR104## in which R⁵ is phenyl, phenyl having 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl, F, Cl, Br, I, C₁ -C₄ alkoxy and nitro on the phenyl ring, phenylmethyl, phenylmethyl having 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl, F, Cl, Br, I, C₁ -C₄ alkoxy and nitro on the phenyl ring, phenylmethyl having methylene substituted with halogen, hydroxy, hydroxyimino, C₁ -C₄ alkoxyimino or amino, phenoxymethyl, phenoxymethyl having 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl, F, Cl, Br, I, C₁ -C₄ alkoxy and nitro on the phenyl ring, benzoyl, or benzoyl having 1 to 3 substitutents selected from the group consisting of C₁ -C₄ alkyl, F, Cl, Br, I, C₁ -C₄ alkoxy and nitro on the phenyl ring, or R¹ or R² are carbonyl when taken together with the carbon atom in the azetidinone ring, R⁴ is as defined in claim 1, and R⁹ is said heterocyclic residue selected from the group consisting of thiazol-2-yl, thiadiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, benzimidazol-2-yl, pyrimidin-2-yl and 2-pyridyl, or said heterocyclic residue having 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl, phenyl, C₁ -C₄ alkoxy, nitro and halogen.
 3. A process as defined in claim 1 in which R³ in the compound of the formula (VII) is phenyl or phenyl having 1 to 3 substituents selected from the group consisting of C₁ -C₄ alkyl, F, Cl, Br, I, C₁ -C₄ alkoxy and nitro on the phenyl ring.
 4. A process as defined in any one of claims 1 to 3 in which about 1 to about 5 moles of the compound of the formula (VII) is used per mole of the compound of the formula (VI).
 5. A process as defined in any one of claims 1 to 3 in which the reaction system contains as a catalyst at least one compound selected from:(a) a sulfinic acid represented by the formula

    R.sup.3 SO.sub.2 H                                         (VIII)

(wherein R³ is as defined above) or a salt thereof, (b) a thiol represented by the formula

    R.sup.9 SH                                                 (IX)

(wherein R⁹ is as defined above) or a salt thereof and (c) a nucleophilic compound selected from the group consisting of water, alkali metal hydroxide, alcohol having 1 to 4 carbon atoms or a salt thereof, phenol optionally substituted with methyl, methoxy or nitro or a salt thereof, lower alkyl thiol or a salt thereof, thiophenol optionally substituted with methyl or nitro or a salt thereof, lower alkyl sulfinic acid or a salt thereof, and lower alkyl carboxylic acid or a salt thereof.
 6. A process as defined in claim 5 in which the catalyst is used in an amount of about 0.0001 to about 0.1 mole per mole of the compound of the formula (VI).
 7. A process as defined in any one of claims 1 to 3 in which the reaction is conducted at a temperature ranging from -20° C. to the temperature at which the solvent used is refluxed. 